Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth.
Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth.
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DOI：
10.1126/scisignal.2000431
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发表时间：
2009-11-17
影响因子：
7.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Hitosugi T;Kang S;Vander Heiden MG;Chung TW;Elf S;Lythgoe K;Dong S;Lonial S;Wang X;Chen GZ;Xie J;Gu TL;Polakiewicz RD;Roesel JL;Boggon TJ;Khuri FR;Gilliland DG;Cantley LC;Kaufman J;Chen J
Warburg效应描述了一种促癌代谢开关，即癌细胞比正常组织吸收更多的葡萄糖，即使在氧气存在的情况下，也有利于葡萄糖的不完全氧化。为了更好地理解酪氨酸激酶信号是如何调节Warburg效应的，我们进行了磷酸化蛋白质组学研究。酪氨酸激酶信号在肿瘤中普遍增加。我们发现致癌形式的成纤维细胞生长因子受体1型通过PKM2酪氨酸残基105 （Y105）的直接磷酸化抑制丙酮酸激酶M2 （PKM2）异构体。这通过破坏PKM2辅因子果糖-1,6-二磷酸的结合抑制活性四聚体PKM2的形成。此外，我们发现PKM2 Y105的磷酸化在人类癌症中很常见。PKM2突变体中，苯丙氨酸取代癌细胞中的Y105 (Y105F)，导致缺氧条件下细胞增殖下降，氧化磷酸化增加，乳酸生成减少，裸鼠异种移植肿瘤生长减少。我们的研究结果表明，酪氨酸磷酸化调节PKM2为肿瘤细胞提供代谢优势，从而促进肿瘤生长。
The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y105). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y105 is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth.
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影响因子：
46.9
作者：
Rush, J;Moritz, A;Comb, MJ
通讯作者：
Comb, MJ
DOI：
10.1073/pnas.0404438101
发表时间：
2004-10-05
影响因子：
11.1
作者：
Chen, J;DeAngelo, DJ;Gilliland, DG
通讯作者：
Gilliland, DG
影响因子：
8.8
作者：
Luqmani, Y A;Graham, M;Coombes, R C
通讯作者：
Coombes, R C
影响因子：
2.1
作者：
Shimada, Nobukazu;Shinagawa, Toshie;Ishii, Shunsuke
通讯作者：
Ishii, Shunsuke
影响因子：
3.7
作者：
Hathurusinghe, Harsha R.;Goonetilleke, Kolitha S.;Siriwardena, Ajith K.
通讯作者：
Siriwardena, Ajith K.